Abstract
Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin’s central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD) in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity. We previously reported that the native MARTX toxin effector domain repertoire is dispensable for epithelial cellular necrosis in vitro, but essential for cell rounding and apoptosis prior to necrotic cell death. Here we use an intragastric mouse model to demonstrate that the effector domain region is required for bacterial virulence during intragastric infection. The MARTX effector domain region is essential for bacterial dissemination from the intestine, but dissemination occurs in the absence of overt intestinal tissue pathology. We employ an in vitro model of V. vulnificus interaction with polarized colonic epithelial cells to show that the MARTX effector domain region induces rapid intestinal barrier dysfunction and increased paracellular permeability prior to onset of cell lysis. Together, these results negate the inherent assumption that observations of necrosis in vitro directly predict bacterial virulence, and indicate a paradigm shift in our conceptual understanding of MARTX toxin function during intestinal infection. Results implicate the MARTX effector domain region in mediating early bacterial dissemination from the intestine to distal organs–a key step in V. vulnificus foodborne pathogenesis–even before onset of overt intestinal pathology.
Highlights
The United States Department of Agriculture (USDA) reports that 1 in 6 Americans fall ill with a foodborne infection every year, resulting in more than 3000 fatalities and an estimated $15 billion in economic burden due to combined medical costs, productivity loss, and death
V. vulnificus produces a Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin, which plays a significant role in bacterial virulence
We use a mouse model to show that a region of the MARTX toxin–the effector domain repertoire–is required for bacterial virulence
Summary
The United States Department of Agriculture (USDA) reports that 1 in 6 Americans fall ill with a foodborne infection every year, resulting in more than 3000 fatalities and an estimated $15 billion in economic burden due to combined medical costs, productivity loss, and death. Of the cited foodborne illnesses, the most economically costly on a per-case basis are those caused by the Gram-negative, marine bacterial pathogen Vibrio vulnificus [1]. V. vulnificus cases remain rare, annual V. vulnificus case counts have increased over the past 15 years in the United States, and the infection is prevalent in endemic countries, including Japan, Taiwan, and South Korea [5, 11, 12]. The rise in V. vulnificus infection incidence, while in part attributable to improved reporting, correlates with increasing sea surface temperature and incidence of this disease is expected to increase with climate change [5, 15]
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